1. Field
The present disclosure relates to new thiazole analog compounds and their pharmaceutically acceptable salts; pharmaceutical compositions comprising the new thiazole analog compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new thiazole analog compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cellular proliferative diseases, such as cancer, and in particular cancer presenting as metastatic tumors.
2. Description of Related Art
Metastasis is the major cause of death in cancer patients: nearly 90% mortality has been attributed to metastatic spread of the disease rather than to the primary tumor. See, e.g., Chambers, A. F.; Groom, A. C.; MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2002; 2:563-572; Fidler, I. J. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Rev Cancer. 2003; 3:453-458; and Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: the next generation. Cell. 2011; 144:646-674. Decades of intensive research have focused on the search for therapeutic solutions targeting cancer cell migration and invasion, and angiogenesis. See Weiss, L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev. 2000; 19:193-383.
Metastasis is a complex process, involving multiple steps that include cancer cell motility, intravasation, transit and survival in the circulation, extravasation, and growth at a new site. While in theory, inhibition of any of these metastatic stages will prevent the formation of tumors at remote sites, clinically the window of opportunity to block metastasis may not be as optimal as one might hope for. See Chambers, A. F.; MacDonald, I. C.; Schmidt, E. E; Morris, V. L.; Groom, A. C. Clinical targets for anti-metastasis therapy. Adv Cancer Res. 2000; 79:91-121. For example, stages involving cancer cell survival in the circulation, arrest and extravasation, may not be ideal targets for development of therapeutic solutions, as these processes appear to occur relatively fast, in large numbers, and are less vulnerable to drug interference. On the other hand, growth of cancer cells in secondary sites takes much longer to cause irreversible damage, thus offering a broader time window for prevention of metastasis. See Chambers 2000, and Epstein, R. J. Maintenance therapy to suppress micrometastasis: the new challenge for adjuvant cancer treatment. Clin Cancer Res. 2005; 11:5337-5341.
Small molecule drugs, such as matrix metalloproteinases (MMP) inhibitors (see Overall, C. M.; Lopez-Otin, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev. Cancer 2002; 2:657-672) and tubulin targeted inhibitors (see Jordan, M. A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer 2004; 4:253-265), have been developed to block metastasis. So far these drugs have had only limited clinical success. Most chemotherapies target cancer cell proliferation as a means to inhibit dissemination, leading to toxicity to healthy cells, as well as acquired resistance in cancer cells. The metastasis modifying processes, however, may be more effectively influenced by long term treatment of non-cytotoxic drugs such as protease inhibitors, chemokine antagonists, kinase blockers, adhesion modifiers, and anti-inflammation agents. See Epstein, 2005. The search for improved, more potent, and less toxic drugs for metastasis intervention remains an ongoing effort.
For the foregoing reasons, there is therefore a great need in the art for new drugs capable of treating cellular proliferative diseases, which are especially suited for disrupting the metastatic processes of cancerous cells.
The solution to this technical problem is provided by the embodiments characterized in the claims.